ObjectiveThe purpose of this study was to find a new method for the treatment of drug-resistant epilepsy, and to study the efficacy and safety of Bacteroidesfragilis (BF839) in the adjunctive treatment of refractory epilepsy, as well as the improvement of comorbidity.MethodsA prospective, single-arm, open pilot clinical study was designed for the additive treatment of drug-resistant epilepsy using BacteroidesFragilis 839 (BF839). 47 patients with refractory epilepsy, who were admitted to the epilepsy outpatient clinic of the Second Affiliated Hospital of Guangzhou Medical University from April 2019 to October 2019, were enrolled and treated with BF839 adjunct treatment. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week treatment period. Other efficacy analysis included response rate(proportion of patients with ≥ 50% seizure reduction) in the 16 weeks period, the proportion of patients seizure free and the retention rate after12 months intervention, and the observance of the side effects and comorbidities.ResultsThe median reduction percent of all seizure types was −53.5% (P=0.002). The response rate was 61.1% (22/36). 8.5% (4/47) patients seizure free at 12 months. The retention rate at 12 months was 57.4% (27/47). The side effects were diarrhea 4.3% (2/47) and constipation 4.3% (2/47). 48.9% (23/47) of the patients reported improvement in comorbidities, with cognitive improvement of 21.2% (10/47).ConclusionBF839 can be used as an effective additive therapy to treat drug-resistant epilepsy. It is safe and beneficial to the improvement of comorbidities. This is the first time in the world that a single intestinal strain has been reported to be effective in treating drug-resistant epilepsy. This research has important implications.